Nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) and their effects on signaling in the nucleus accumbens (NAc) are important for the behavioral actions of nicotine related to addiction. Our hypothesis is that there is a dissociation between nicotine reward and locomotor activation. We hypothesize that nicotine reward necessitates activation of D1 receptors and increased CREB activity in the NAc shell, whereas DA receptor activation in the NAc core is sufficient for locomotor activation, and CREB activity is not necessary. We have used transgenic mice with expression of the beta2-subunit of the nAChR on VTA neurons that project to the NAc core to test the idea that these receptors are sufficient for nicotine-dependent locomotor activation. Preliminary studies show that these mice show relatively normal nicotine-dependent locomotor activation but do not show a place preference for nicotine or activation of CREB in the NAc core.
Aim 1 of this project will be to determine whether CREB activity in the NAc shell, but not core, is critical for nicotine reward using viral-mediated gene transfer and complementary pharmacological approaches. In addition we will determine whether the balance between D1 vs. D2 signaling is important for CREB activity in the NAc shell or core, and nicotine reward.
Aim 2 will determine whether DA release in the NAc core and not the shell is sufficient for nicotine-mediated locomotor activation, and determine the subsequent effects on CREB activation in the NAc. These experiments are significant because they could explain the very sharp dose-response function for nicotine reward and may provide new points of intervention to support smoking cessation. They will help identify the molecular mechanisms and signaling pathways involved in nicotine locomotion and reward, and determine the role of D1 and D2 receptor activation in these behaviors. These studies will test the hypothesis that CREB activity in the NAc shell integrates D1 and D2 signaling and is a critical output underlying nicotine reward.

Public Health Relevance

We know that nicotine is the primary agent in tobacco that leads to addiction. Nicotine changes the strength of communication between nerve cells and this is thought to be responsible for the long-term changes in behavior that results from smoking, including long-lasting increases in cigarette craving and the likelihood to relapse. We have shown that activity of CREB, a molecule that is known to be important for changing the connections between nerve cells, is necessary for nicotine to be rewarding in mice. We have also shown using genetically-manipulated mice that nicotine receptors on a group of nerve cells in the brain's reward center that communicate with what is called the core of the nucleus accumbens are sufficient for the ability of nicotine to act as a stimulant, but not nicotine reward. We believe that nicotine receptors on nerve cells that communicate with the nucleus accumbens shell are important for nicotine reward, whereas nicotine receptors on nerve cells that communicate with the nucleus accumbens core are important for nicotine's stimulant properties. These two pathways can be distinguished genetically, but may also be sensitive to different drugs. We propose that targeting the molecules that lead to long- lasting changes in the communication between nerve cells in the nucleus accumbens shell could lead to new therapies for smoking cessation.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pollock, Jonathan D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Park, Joongkyu; Chávez, Andrés E; Mineur, Yann S et al. (2016) CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory. Neuron 92:75-83
McClure-Begley, Tristan D; Esterlis, Irina; Stone, Kathryn L et al. (2016) Evaluation of the Nicotinic Acetylcholine Receptor-Associated Proteome at Baseline and Following Nicotine Exposure in Human and Mouse Cortex. eNeuro 3:
Jung, Yonwoo; Hsieh, Lawrence S; Lee, Angela M et al. (2016) An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior. Nat Neurosci 19:905-14
Lewis, Alan S; Oberleitner, Lindsay M S; Morgan, Peter T et al. (2016) Association of Cigarette Smoking With Interpersonal and Self-Directed Violence in a Large Community-Based Sample. Nicotine Tob Res 18:1456-62
Picciotto, Marina R; Lewis, Alan S; van Schalkwyk, Gerrit I et al. (2015) Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states. Neuropharmacology 96:235-43
Zhou, Wen-Liang; Gao, Xiao-Bing; Picciotto, Marina R (2015) Acetylcholine Acts through Nicotinic Receptors to Enhance the Firing Rate of a Subset of Hypocretin Neurons in the Mouse Hypothalamus through Distinct Presynaptic and Postsynaptic Mechanisms(.) eNeuro 2:
Lewis, Alan S; Mineur, Yann S; Smith, Philip H et al. (2015) Modulation of aggressive behavior in mice by nicotinic receptor subtypes. Biochem Pharmacol 97:488-97
Mineur, Yann S; Einstein, Emily B; Bentham, Matthew P et al. (2015) Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine. Neuropsychopharmacology 40:938-46
McKee, Sherry A; Potenza, Marc N; Kober, Hedy et al. (2015) A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation. J Psychopharmacol 29:300-11
Mineur, Yann S; Taylor, Seth R; Picciotto, Marina R (2014) Calcineurin downregulation in the amygdala is sufficient to induce anxiety-like and depression-like behaviors in C57BL/6J male mice. Biol Psychiatry 75:991-8

Showing the most recent 10 out of 67 publications